The present disclosure provides compounds useful for the inhibition of KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C. The compounds have a general Formula I′: wherein the variables of Formula I′ are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, cancer.
Legal claims defining the scope of protection, as filed with the USPTO.
. The compound or salt of, wherein Z is N and Q is CH or Z is C—F and Q is CH.
. The compound or salt of, wherein L is-O-methylene-, —O-ethylene-, —O-n-propylene or —O-isopentanylene and L is substituted with 0-2 occurrences of R.
-. (canceled)
. The compound or salt of, wherein n is 1 and m is 1 or n is 1 and m is 2 or n is 2 and m is 1.
. The compound or salt of, wherein X is O.
. The compound or salt of, wherein X is CH.
. The compound or salt of, wherein n is 0 and m is 1; n is 1 and m is 0; n is 1 and m is 1; n is 1 and m is 2 or n is 2 and m is 1.
-. (canceled)
. The compound or salt of, wherein -L-L- is —O—C(O)—O-L.
. The compound or salt of, wherein Lis ethylene, n-propylene, 2-methyl-n-propylene, cis-2-propenylene, trans-2-propenylene or —CH-cyclopropylene.
-. (canceled)
. The compound or salt of, wherein -L-L- is a —Chydroxyalkylene-5-6 membered heteroaryl-L.
. The compound or salt of, wherein Lis ethylene.
. The compound or salt of, wherein -L-L- is —Calkylene-O-L.
. The compound or salt of, wherein -L-L- is -methylene-O-L.
. The compound or salt of, wherein Lis n-butylene, 2,2-difluoro-n-butylene, trans-2-butenylene, cis-2-butenylene, 3-methyl-n-butylene, -ethylene-cyclopropylene- or ethylene-O-methylene.
. (canceled)
. The compound or salt of, wherein -L-L- is ethylene-O-L.
. The compound or salt of, wherein Lis ethylene, n-propylene or methylene-cyclopropylene.
. (canceled)
. The compound or salt of, wherein -L-L- is —NR—C(O)—O-L.
. The compound or salt of, wherein Ris hydrogen or methyl.
. The compound or salt of, wherein Lis n-propylene, ethylene, —CH-cyclopropylene.
-. (canceled)
. The compound or salt of, wherein -L-L- is —C(O)—.
. The compound or salt of, wherein Lis n-propylene, -methylene-O-n-propylene or n-butylene.
. (canceled)
. The compound or salt of, wherein Ris Calkyl or halogen.
. The compound or salt of, wherein Ris fluorine.
. (canceled)
. (canceled)
. A pharmaceutical composition comprising the compound or salt according ofand a pharmaceutically acceptable excipient.
-. (canceled)
. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according ofor a pharmaceutical composition according to.
. (canceled)
. The method according to, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
. The method according to, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
. The method according to, wherein the cancer is non-small cell lung cancer.
. The method according to, wherein the cancer is colorectal cancer.
. The method according to, wherein the cancer is pancreatic cancer.
. (canceled)
Complete technical specification and implementation details from the patent document.
This application claims the benefit of U.S. Provisional Patent Application No. 63/383,674, filed Nov. 14, 2022, U.S. Provisional Patent Application No. 63/497,978, filed Apr. 24, 2023 and U.S. Provisional Patent Application No. 63/582,751, filed Sep. 14, 2023, each of which is incorporated by reference in its entirety.
The present disclosure provides compounds braving activity as inhibitors of mutant KRAS proteins. This disclosure also provides pharmaceutical compositions comprising the compounds, uses and methods of treating certain disorders, such as cancer, including but not limited to non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
From its identification as one of the first human oncogenes in 1982 (Der et al., 1982), KRAS (the Kirsten rat sarcoma viral oncogene homologue) has been the focus of extensive academic and industrial research, as a key node in the MAPK signal transduction pathway, as a transforming factor in a network of parallel effector pathways (e.g. PI3K/AKT) (Vojtek et al., 1998) and as a potential target for anti-cancer agents (Malumbres et al., 2003). Despite progress in the development of inhibitors of upstream and downstream nodes in the MAPK pathway (e.g., EGFR (Sridhar et al., 2003), BRAF (Holderfield et al., 2014) and MEK (Caunt et al., 2015), the KRAS protein has historically proven resistant to direct inhibition.
KRAS is a O-protein that couples extracellular mitogenic signaling to intracellular, pro-proliferative responses. KRAS serves as an intracellular “on/off” switch. Mitogen stimulation induces the binding of OTP to KRAS, bringing about a conformational change which enables the interaction of KRAS with downstream effector proteins, leading to cellular proliferation. Normally, pro-proliferative signaling is regulated by the action of GTPase-activating proteins (GAPs), which return KRAS to its GDP-bound, non-proliferative state Mutations in KRAS impair the regulated cycling of KRAS between these GDP- and GTP-bound states, leading to the accumulation of the GTP-bound active state and dysregulated cellular proliferation (Simanshu et al., 2017).
Attempts to develop inhibitors of mutated KRAS proteins have historically been thwarted by the absence of druggable pockets on the surface of the protein (Cox et al., 2014). In 2013, Shokat and colleagues identified covalent inhibitors of a common (O'Bryan, 2019) oncogenic mutant of KRAS, KRAS G12C, which bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevented its subsequent activation (Ostream et al., 2013). This discovery brought about significant new efforts in the KRAS inhibitor research, which have recently culminated in the entry of KRAS inhibitors in human clinical trials.
While some progress has been made on KRAS G12C inhibitors, there is a continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of other KRAS such as KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C. Thus, there is a need to develop new inhibitors for KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C for the treatment of disorders, such as cancer.
In a first aspect, the present application is directed to compound of formula (I′):
In a second aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable excipient.
In a third aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition as described herein for use in treating cancer (e.g., non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma).
Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims.
Provided herein as embodiment 1 is a compound of formula (I′):
Provided herein as embodiment 2 is the compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having one additional oxygen heteroatom. Provided herein as embodiment 3 is the compound or salt according to embodiment 2, wherein p is 0. Provided herein as embodiment 4 is the compound or salt according to embodiment 3, wherein B-Lis
Provided herein as embodiment 5 is the compound or salt according to embodiment 4, wherein B-Lis
Provided herein as embodiment 6 is the compound or salt according to embodiment 5, wherein B-Lis
Provided herein as embodiment 7 is the compound or salt according to embodiment 6, wherein
Provided herein as embodiment 8 is the compound or salt according to embodiment 6, wherein
Provided herein as embodiment 9 is the compound or salt according to embodiment 6, wherein
Provided herein as embodiment 10 is the compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having one additional nitrogen heteroatom. Provided herein as embodiment 11 is the compound or salt according to embodiment 10, wherein p is 0. Provided herein as embodiment 12 is the compound or salt according to embodiment 11, wherein B-Lis
Provided herein as embodiment 13 is the compound or salt according to embodiment 12, wherein B-Lis
Provided herein as embodiment 14 is the compound or salt according to embodiment 13, wherein B-Lis
Provided herein as embodiment 15 is the compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having 0 additional heteroatoms. Provided herein as embodiment 16 is the compound or salt according to embodiment 15, wherein p is 0. Provided herein as embodiment 17 is the compound or salt according to embodiment 16, wherein B-Lis
Provided herein as embodiment 18 is the compound or salt according to embodiment 17, wherein B-Lis
Provided herein as embodiment 19 is the compound or salt according to embodiment 18, wherein B-Lis
Provided herein as embodiment 20 is the compound or salt according to embodiment 18, wherein B-Lis
Provided herein as embodiment 21 is the compound or salt according to embodiment 18, wherein B-Lis
Provided herein as embodiment 22 is the compound or salt according to embodiment 18, wherein B-Lis
Provided herein as embodiment 23 is the compound or salt according to embodiment 1, wherein B is a 4-10 membered heterocycloalkyl having one additional oxygen heteroatom. Provided herein as embodiment 24 is the compound or salt according to embodiment 23, wherein p is 1. Provided herein as embodiment 25 is the compound or salt according to embodiment 24, wherein B-Lis
Provided herein as embodiment 26 is the compound or salt according to embodiment 24 or 25, wherein Ra is Calkyl, Chaloalkyl or Cdeuteroalkyl. Provided herein as embodiment 27 is the compound or salt according to embodiment 26, wherein Ris methyl, CDor monofluoromethyl.
Provided herein as embodiment 28 is the compound or salt according to embodiment 27, wherein B-Lis
Provided herein as embodiment 29 is the compound or salt according to embodiment 28, wherein B-Lis
Unknown
October 2, 2025
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